No abstract

BACKGROUND: Ichthyosis vulgaris is the most common type of Mendelian disorders of cornification, caused by loss-of-function mutations in the gene encoding epidermal protein filaggrin (FLG), namely R501X and 2282del4. FLG 2282del4 mutation in heterozygotes is incompletely penetrant. Polymorphisms in one-carbon metabolism genes could be associated with clinical manifestation of ichthyosis vulgaris. AIM: The purpose of the present study was to analyze the effects of MTHFR, MTR and MTRR polymorphisms in patients with ichthyosis vulgaris. METHODS: 31 patients with ichthyosis vulgaris, 7 their FLG heterozygous relatives without symptoms of disorder, and 150 healthy controls were enrolled in study. FLG null mutations —R501X (rs61816761) and 2282del4 (rs558269137) — and one-carbon metabolism gene polymorphisms — MTHFR C677T (rs1801133), MTHFR A1298C (rs1801131), MTR A2756G (rs1805087) and MTRR A66G (rs1801394) — were analyzed by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: Among patients with ichthyosis, heterozygous for FLG 2282del4 mutation, the distributions of genotypes for folate metabolism genes were: MTHFR C677T CC:CT:TT —29.4%:70.6%:0.0%; MTHFR A1298C AA:AC:CC — 52.9%:47.1%:0.0%; MTR A2756G AA:AG:GG — 70.3%:23.5%:5.9%; MTRR A66G AA:AG:GG — 23.4%:52.9%:23.5%. The frequencies of MTR 2756AA and MTRR 66GG genotypes were 1.4–1.6 times higher in affected individuals heterozygous for 2282del4 than in patients with other FLG genotypes. In affected 2282del4 heterozygotes, the frequency of MTR 2756AA genotype was 1.6 times greater than in healthy controls (p<0.01). The strongest association was found between MTHFR 677CT/MTHFR 1298AA/MTR 2756AA/MTRR 66AG genotype and ichthyosis — OR=11.23 (95% CI 2.51−50.21, p=0.002). CONCLUSIONS: Various genotypes of one-carbon metabolism genes increase the risk of ichthyosis in heterozygotes for the FLG 2282del4 mutation (OR 2.799‑11.231). The most probable predisposing genotype is 677CT/1298AA/2756AA+AG/66AG.